Photodynamic therapy (PDT) is commonly used to treat some types of cancer. PDT involves injecting a photosensitizing agent into the bloodstream of a patient. The agent is absorbed by cells all over the body, but it generally accumulates in the tumour due to abnormalities or defects in the tumour vasculature. It is also rapidly absorbed by cancer cells, which tend to grow and divide much more quickly than healthy cells and hence have a higher metabolic activity.
Approximately 24 to 72 hours after the injection, when most of the agent has left the normal cells but remains in the tumour, only the tumour is exposed to light of a specific frequency, such as UV light or laser light. The photosensitizing agent that has accumulated in the tumour is excited by exposure to this light and reacts with nearby oxygen or water molecules in the tissue to produce reactive oxygen species (ROS), such as singlet oxygen (average lifetime of 3.7 ms and a diffusion distance of 82 nm), a superoxide radical (average lifetime of 50 ms and a diffusion distance of 320 nm) or a hydroxyl radical (average lifetime of 10−7 s and a diffusion distance of 4.5 nm). The ROS produced overwhelm the antioxidant defence capacity of nearby cells thereby resulting in the destruction of cancer cells in the tumour.
The short life-times and diffusion distances of the ROS allow cancer cells to be destroyed with little or no damage being caused to neighbouring healthy cells. In addition to directly killing cancer cells, PDT also appears to shrink or destroy tumours by damaging blood vessels in the tumour, thereby depriving it of nutrients. A further benefit is that PDT may also activate the immune system of the patient to attack the tumour cells.
Titanium dioxide is known to generate ROS on exposure to UV light. In fact, the effect of titanium dioxide on cultured human adenocarcinoma cells after UV irradiation has been investigated (Xu et al., Supramolecular Science, 5 (1998), 449-451). In this study, transmission electron microscopy (TEM) showed disruption to the cellular membrane and endomembrane system of the cells as a result of oxidative stress. It is believed that the titanium dioxide particles produce hydroxyl radicals that oxidize the membrane lipids of the cells to produce peroxidants, which then set up a series of peroxidant chain reactions. The oxidatively stressed malignant cells progress to a necrotic state that results in their destruction.
Titanium dioxide and many of the photosensitizing agents used in PDT are excited by light of a specific wavelength that cannot penetrate deep into a human body. Consequently, PDT has been limited to the treatment of superficial cancers, such as skin cancers.
Cancers in other locations of the body may instead be treated using radiotherapy, which involves the use of ionizing radiation, such as X-rays. However, some types of cancer, such as renal cell cancer, are radioresistant because the doses of radiation required to destroy the cancer are too high to be safe in clinical practice. Higher doses of radiation are also associated with an increased risk of causing cancer. There is therefore a need for an agent that will enhance or improve existing radiotherapy treatments.
International patent application no. PCT/FR2005/001145 (WO 2005/120590) describes composite or aggregate particles that are activatable by X-rays. The particles are composed of two distinct inorganic compounds, which are arranged to be near to one another. The first inorganic compound is able to absorb X-rays and then emit UV-visible light. The second inorganic compound can absorb UV-visible light and then generate free radicals on contact with water or oxygen. Such an arrangement of compounds allows X-rays to be used to generate ROS by a stepwise excitation process. However, there are energy losses associated with each excitation step, such that the amount of ROS generated per unit dose of X-rays is relatively low.